This is a resubmission of a five-year competitive renewal of an ongoing programmatic research program of major depressive disorder (MDD) in children and adolescents (previously entitled Childhood Depression: Remission and Relapse). The first three studies were highly productive, demonstrating 1) continuity of the pathophysiology of depression in the pediatric age group, 2) efficacy of fluoxetine over placebo in pediatric depression, and most recently, 3) continued use of fluoxetine beyond acute treatment reduces relapse rates in this population. However, there continue to be major deficits in the research of pediatric depression treatment. Despite several positive RCTs in both psychotherapy and pharmacotherapy with relatively strong response rates (55-65%), remission rates (being well) remain quite low (30-40%). Furthermore, early onset depression is often chronic, leading to high rates of relapse. In our recently completed continuation study, even with continued treatment of fluoxetine, 42% relapsed, with 22% experiencing a complete relapse of depression (CDRS-R =40 with 2 weeks of clinical deterioration). Residual symptoms were associated with higher relapse rates, especially in fluoxetine-treated patients. Although continued medication reduces relapse rates, other continuation phase treatments are needed, with particular emphasis on increasing remission and shortening the time to remission. Adult research suggests that adding cognitive behavioral therapy (CBT) following antidepressant treatment response reduces residual symptoms (which have been associated with lowering relapse rates) and reduces relapse rates. Utilizing the R34 mechanism, the investigators have developed a CBT treatment intervention, which focuses on improving residual symptoms and teaching wellness skills to youth who have responded to an antidepressant (R34 MH72737 Continuation Phase CBT for Youth with MDD; PI: Kennard). We propose to determine if adding psychotherapy (CBT) following antidepressant response will improve remission rates and time to remission, as well as reduce relapse rates in children and adolescents compared to continued medication management. One hundred forty two youth (ages 7-18) with MDD who respond to 6 weeks of fluoxetine will be randomized to continued medication management alone (MM) or a sequential treatment strategy (STS) of medication management plus relapse prevention CBT (RP- CBT) for 6 months. Following randomization, all subjects will be evaluated every six weeks by an independent evaluator for the 6 month continuation phase. Remission is defined as CDRS-R total score =28. Relapse is defined as 1) CDRS-R score =40 with a history of 2 weeks of clinical deterioration or 2) CDRS-R<40, but with significant clinical deterioration. All subjects will be evaluated every 6 months for 1 year after completion of the continuation phase. Depression in youth is an underdiagnosed and undertreated illness, which can lead to long-term deficits in school, family, and overall functioning. Many pharmacological and psychotherapeutic interventions are available for this disorder; however, to date few treatments have been effective in treating youth to remission, or symptom free status, which is important as partial remission is related to relapse of depressive symptoms. The proposed project would test a treatment strategy combining medication treatment with fluoxetine and a new Relapse Prevention Cognitive Behavioral Therapy (RP-CBT) to maximize the benefits of both treatments to result in higher remission rates and reduced relapse rates.